Method of relieving pain and inflammatory conditions employing substituted salicylamides

ABSTRACT

A topically and systemically administered anti-inflammatory composition for human and for veterinary consumption which comprises compounds of the general formula: ##STR1## wherein R 1 , R 2  and R 3  are defined hydrocarbon attachments and Y is --OH or a phenolic ester group derived from the reaction of such --OH group with a carboxylic acid halide or anhydride. 
     In typical compounds covered by said general formula 
     (a) R 1  is H, R 2  is 5,n-octanoyl, Y is hydroxy and R 3  is p-trifluoromethylphenyl; 
     (b) R 1  is H, R 2  is 5,n-decanoyl, Y is hydroxy and R 3  is benzothiazol-2-yl and 
     (c) R 1  is H, R 2  is 5,n-decanoyl, Y is acryloyloxy and R 3  is p-nitrophenyl. 
     The resulting compositions take the form of ointments, solid sticks, tablets, capsules, injectable solutions and suspensions, ear drops, eye drops, nose drops, douches, suppositories, enemas, liniments, gels, lotions, shampoos, soaps, creams, solutions, aerosols, pads, plasters, bandages, dressings and catamenial and non-catamenial tampons. The compositions are useful in relieving pain or inflammation as well as microbial infections in mammals when applied topically to the skin or affected organs or when administered systemically.

This is a divisional application of Ser. No. 525,916 filed Aug. 24, 1983now U.S. Pat. No. 4,560,519.

This invention relates to the novel use of certain secondary amidocompounds including certain salicylanilides as systemic analgesic agentsand also for topical application as anti-inflammatory compositions.

A group of compounds which are known to possess analgesic properties arederivatives of salicylic acid, in particular acetylsalicylic acid whichis more commonly known as aspirin. Aspirin is a widely known andextensively used orally administered antipyretic analgesic. Methylsalicylate, which is closely related thereto is the active ingredient ofoil of wintergreen (Gaultheria procumbens). Oil of wintergreen is usedas a topical analgesic. However, it is interesting to note in thisregard that although topically applied, such use is contraindicated bythe fact that oil of wintergreen is a mild skin irritant. It is usefulfor the treatment of sore muscles and not for the relief of skininflammation per se.

A number of different amido compounds having anti-inflammatory activityhave been reported in "Nature", 222, 275: 1969; "J. Med. Chem.", 14, 973(1971); "J. Med. Chem.", 14, 1171 (1971), "J. Med. Chem.", 15, 551(1972); "J. Med. Chem.", 15, 848 (1972) and in "J. Med. Chem." 16, 493(1973).

U.S. Pat. No. 3,917,617 discloses analgesic, antibacterial, antifungaland antidepressant properties having resorcinol derivatives of theformula: ##STR2## wherein R represents an alkyl group having 1 to 20carbon atoms, an arylalkyl group, or a cycloalkyl-lower alkyl group;

R₁ and R₂ represent hydrogen or the same or different lower alkyl orlower alkanoyl groups; and Z represents --NH₂, --NHR₃, --NR₃ R₄, or##STR3## where R₃ is lower alkyl or phenyl-lower alkyl, R₄ is loweralkyl or phenyl-lower alkyl, m is an integer from 0 to 6, n is aninteger from 0 to 6, m+n is an integer from 3 to 6, and X is CH₂, CHR₃,O, S, or NR₃.

U.S. Pat. No. 3,027,301 discloses inter alia as useful wound healingagents hydroxypropylsalicylamides of the formula: ##STR4## wherein R isa member of the group consisting of hydrogen, hydroxyl, methyl,chlorine, and phenyl, and a pharmaceutical carrier.

French Pat. No. 1,094,578 discloses the use as antiseptics halogenatedsalicylanilides of the formula: ##STR5## wherein X₁ and X₂ are ahydrogen or a halogen atom or a methyl group; Y is a hydrogen or ahalogen atom or a trifluoromethyl group and Z is a hydrogen or a halogenatom.

U.S. Pat. No. 4,287,191 describes compositions effective as antisepticsagainst a wide range of microorganisms, especially those prevalent indental plaque comprising novel 5-acyl-salicylanilides includingcompounds of this invention, of the formula: ##STR6##

In the above formula, Z is a substituted phenyl ring of from 6 to 30carbon atoms including substituents, R is a substituted or unsubstitutedalkyl or phenyl group of from 2 to 30 carbon atoms includingsubstituents and M is a radical selected from the group consisting of--C═N, --F, --NO₂, --H, lower alkyl or lower haloalkyl.

Batista, A. J., "Salicylanilides: Design, Synthesis, and In VitroEvaluation as Inhibitors of Dental Plaque-Forming Microorganisms", Ph.D. Dissertation, State University of New York at Buffalo, 1980 disclosesthe synthesis of and microbiocidal properties of substituted salicylicacids, salicylates and salicylanilides, including compounds employed inthis invention.

It is an object of the present invention to provide methods for therelief of pain and inflammation in human and in veterinary subjects.

It is a further object of the present invention to provide compositionsfor topical and for systemic application in such context.

It is a further object of the present invention to provide suchcompositions of high effectiveness and low toxicity.

It is a further object of the present invention to provide suchcompositions in a wide variety of administration vehicles to enabletopical and systemic application thereof in a correspondingly wide rangeof applications.

These and other objects will become apparent on further reading of thisspecification.

In a composition aspect, this invention relates to anti-inflammatorycompositions which comprise, in admixture with a pharmaceuticallyacceptable carrier vehicle, an anti-inflammatorily effective amount of acompound of the formula: ##STR7## bearing on the benzene ring at leastone lipophilic substituent which imparts to the compound a distributioncoefficient in octanol/water of about 4.5 to about 10 wherein thesubstituents --R₁ and --R₂ are --H, normal or branched chain or cyclicor fused ring polycyclic or non-fused ring polycyclic, alkyl, alkenyl,alkynyl, aryl or heteroaryl groups optionally containing furthersubstituents thereon, said --R₁ and --R₂ substituents comprising up toabout 30 carbon atoms when taken together either attached directly tothe phenyl ring or through a ##STR8## group with the proviso that atleast one of --R₁ and --R₂ is other than --H; and wherein --R₃ isselected from the group consisting of thiazol-2-yl, benzothiazol-2-yland R₄ -substituted phenyl, i.e., of the formula: ##STR9## wherein --R₄is selected from the group consisting of --CH₂ R₅, --OH, --COOH, thetautomeric pair ##STR10## --CH₂ COOH, --COOCH₃, --COOC₂ H₅, --CH₂COOCH₃, --CH₂ COOC₂ H₅, --NO₂, CX₁ X₂ X₃ wherein X₁, X₂ and X₃ arehalogen atoms, which can all be different halogen atoms or wherein twoor more halogen atoms are alike, wherein --R₅ is H, alkyl, cycloalkyl,or their unsaturated counterparts, aryl or heteroaryl comprising up to atotal of about 24 carbon atoms. Alternatively, --R₃ may simply be anyaryl or heteroaryl group or a secondary amido ligand --CH₂ --R₆ wherein--R₆ is --H or an attachment of up to 24 carbon atoms of the samedescription as --R₁ or --R₂ involving the same linking groups betweenitself and the methylene group directly attached to the amido nitrogenatom.

In the Formula I shown above, alkyl can be straight or branched chain,e.g., n-octyl, n-decyl or tert-butyl; cycloalkyl can be monocyclic,e.g., ##STR11## fused polycyclic, e.g., ##STR12## or non-fusedpolycyclic, e.g., ##STR13## alkenyl can be, e.g., CH₂ ═CH₂ --(CH₂)_(n)-- where n is an integer or CH₃ --(CH₂)_(n) CH═CH(CH₂)_(m) -- where nand m are each either zero or an integer it being understood that one ormore double bonds may be included in the formula;

alkynyl can be, e.g., HC.tbd.C-- or CH₃ (CH₂)_(n) --C.tbd.C--(CH₂)_(m)-- where m and n are each zero or an integer it being understood thatone or more triple bonds may be included in the formula;

aryl can be mono or polycyclic, e.g., ##STR14## and heteroaryl can bemono or polycyclic and can contain 1, 2, 3 or more heteroatoms, e.g., N,O or S, e.g., ##STR15##

Each of the respective groups can bear one or more substituents suchthat --R₁ and --R₂ taken together contain collectively up to about 30carbon atoms and --R₃ contains up to about 25 carbon atoms. It willtherefore be understood that the examples given are only illustrativeand not limitative of the invention.

In one method of use aspect, this invention relates to a method ofalleviating pain in mammals, particularly human subjects by the systemicadministration of a composition comprising a compound or compounds ofFormula I.

In another method of use aspect, this invention relates to a method fortreating dermatological inflammation and pain which comprises topicalapplication of a composition comprising a compound or compounds ofFormula I over areas of said dermatological inflammation in mammals,particularly human beings over a therapeutically effective length oftime.

In yet another method of use aspect, this invention relates to a methodof alleviating pain and inflammation in mammalian organs and bodycavities such as the ear, eye, nose, vagina, anus and rectum.

The compounds of Formula I may be incorporated (without limitation) inpetroleum jelly, lanolin, paraffin wax, alkanols and mixtures thereof aswell as other comparable vehicles noted in the succeeding Examples.Alternative vehicles include, without limitation ointments, sticks,capsules and tablets, injection solutions or suspensions, othersolutions, shampoos, soaps, creams, water, aerosol bases, medicatedpads, medicated plasters, medicated bandages, medicated dressings, andmedicated catamenial and non-catamenial tampons. Incorporation of thecompounds of Formula I in suitable carriers also results in ear drops,eye drops, nasal drops, anal and vaginal suppositories, enemas anddouches as well as liniments, gels and lotions. The foregoig generalexamples as well as the specific Examples noted below are illustrativeand not limitative of this invention.

The medicated articles are placed in intimate contact with the affectedorgan or the medicated compositions applied to the affected skin,mucuous membrane or organ for a sufficient length of time to relievepain with repeat applications as needed. By making such use of thecompounds of Formula I, pain and inflammation in, e.g., the ear, eye,nose, anus and vagina or any other affected organ or cavity arerelieved.

Topical application on the skin of the compounds of Formula I in theform e.g. of ointments, sticks, shampoos, soaps, creams, water and othersolutions, aerosol bases, medicated pads, medicated plasters, medicatedbandages, medicated dressings, liniments, gels and lotions results inthe relief of skin inflammation and pain. The skin inflammation treatedby this invention can be the result of various skin disorders such aseczema, psoriasis, seborrheic dermatitis, contact dermatitis, allergicdermatitis, reactions due to poison ivy, poison oak, stinging nettles,etc. Further included within the purview of this invention andillustrative but not limitative thereof are skin inflammation caused bytissue damage resulting from ultraviolet or other electromagneticradiation including sunburns, insect and kindred bites and stings aswell as thermal burns.

The preferred salicylamides of Formula I have an octanol/waterdistribution coefficient greater than 4.5 and the substituted moieties--R₄ in the phenyl ring of the secondary amido ligand (when the --R₃ligand takes the form --PhR₄, Ph being a phenyl ring) have a combinedoverall electron withdrawing effect on said phenyl ring.

The term "distribution coefficient" of a composition as used herein isthe log₁₀ P where P is the ratio of the concentration of the compositionin octanol to the concentration of the composition in water in a twophase octanol-water system. A distribution coefficient of, e.g., 5therefore means that the ratio of the concentration of the compound inoctanol to the concentration in water is 10⁵ or 100,000 to 1. Thedistribution coefficient is a measure of the lipophilic character of thecompound. The preferred compounds of Formula are lipophilic as indicatedby a distribution coefficient of greater than about 4.5. Thedistribution coefficient is however usually less than 10.

The preferred compounds of Formula I are those of the structure shownbelow: ##STR16## wherein n is an integer, preferably from 3 to 14, R₃ isas defined above and X is ##STR17## or a covalent bond joining the alkylgroup to the phenyl ring. When --R₃ is an R₄ -- substituted benzenering, R₄ -- preferably is para --NO₂, meta --COOC₂ H₅ or meta or para--CF₃.

Of the preferred compounds, especially preferred are those wherein:

(a) n is 8, X is ##STR18## and --R₃ is a para-nitrophenyl, (hereinaftercalled AN-10),

(b) n is 6, X is ##STR19## and --R₃ is a para-trifluoromethylphenyl(hereinafter called APCF3-8),

(c) n is 6, X is ##STR20## and --R₃ is a meta-trifluoromethylphenyl(hereinafter called AMCF3-8),

(d) n is 5, X is a covalent bond and --R₃ is a paranitrophenyl(hereinafter called SAN-6),

(e) n is 3, X is a covalent bond and --R₃ is a metatrifluoromethylphenyl(hereinafter called S-4-F),

(f) n is 7, X is ##STR21## and --R₃ is meta-carbethoxyphenyl(hereinafter called ACBXE-9),

(g) n is 8, X is ##STR22## and --R₃ is benzothiazol-2-yl (hereinaftercalled ABC-4), and

(h) n is 14, X is ##STR23## and --R₃ is thiazol-2-yl (hereinafter calledRV-19),

(i) n is 8, X is ##STR24## --R₃ is a para-nitrophenyl and the --OH groupof Formula I is replaced with a CH₂ ═CH--COO-- group (hereinafter calledacryloyl AN-10).

The salicylamides of Formula I have analgesic and anti-inflammatoryactivity. The preferred salicylamides have excellent analgesicproperties and many of them exhibit low toxicity in mammals.

The salicylamides of the above formulae are as already noted above, alsouseful for relieving dermal inflammation. The treated dermalinflammation or painful condition is the result of disorders such as ordue to eczema, psoriasis, seborrheic dermatitis, contact dermatitis,allergic dermatitis, reactions due to poison ivy, poison oak andstinging nettles, etc. and sunburns, thermal burns, otherelectromagnetic radiation burns, insect and kindred bits and strings.The foregoing list of disorders and conditions is only illustrative butnot limitative of the invention.

Likewise, such compositions may be administered systemically to relievepain at sites which are only reached or preferentially reached byanalgesic compositions administered systemically. The term "systemicadministration" as used herein includes oral administration, parenteraladministration (including administration by way of intramuscular,subcutaneous, intraarticular and intravenous injections) and throughbody cavities such as the ear, nose, eye, vagina and anus.

It is understood that the use of compositions or articles containing thecompounds of Formula I in the mucous membranes of e.g. the nose andvagina are a form of topical administration.

The method in accordance with the present invention for relieving dermalinflammation whether in human subjects or in veterinary applicationscomprises contacting the affected skin or organ with a salicylamide ofFormula I suspended in a pharmaceutically acceptable carrier vehicle.Likewise, as already noted above, when it is therapeuticallyadvantageous to do so, systemic administration of a compound of FormulaI may be employed as a further method within the scope of thisinvention. Such a carrier vehicle constitutes a compatible spreadablebase and may be one selected from the group consisting of petroleumjelly, lanolin, paraffin wax, alkanols and mixtures thereof. Further,non-limiting examples of compatible spreadable bases are describedwithin the illustrative Examples included in this specification.

When a salicylamide of Formula I is suspended in a hard base such asparaffin wax, a stick for topical application to the affected areas isobtained. Likewise, when the carrier vehicle is a soft pasty substancelike lanolin or petroleum jelly, an ointment suitable for dispensingfrom a collapsible tube is obtained. Advantageously, said compounds maybe incorporated into solution, aerosol, cream, lotion, ointment,liniment, gel, shampoo, soap, suppository, or liquid bases to formsolutions, aerosols, creams, lotions, ointments, liniments, gels,shampoos, soaps, suppositories (vaginal and anal), ear, eye, and nosedrops, enemas, douches and injectable solutions and suspensions.Likewise, incorporation of such compositions in pads, plasters,bandages, dressings, catamenial and non-catamenial tampons results inmedicated pads, medicated plasters, medicated bandages, medicateddressings and medicated tampons (catamenial and non-catamenial) all foruse in the practice of this invention.

Very small concentrations of a salicylamide of Formula I in anacceptable carrier vehicle are effective, with concentrations of about0.1 microgram to about 50 micrograms per milliliter of carrier vehiclebeing sufficient in most cases.

In topical applications of a salicylamide of Formula I, a very shortcontact time of e.g. 10 seconds may be sufficient. If necessary, thecontact time is extended to about 24 hours. Also, if necessary, suchtopical application is repeated, as needed.

It is a further advantage of the invention that the analgesic nature ofthe salicylamides of Formula I, together with their low toxicity maketheir systemic use possible both in human subjects and in veterinaryapplications. The toxicity thereof as measured by the designation LD₅₀has been found, in oral administration in rats to be about 2.0 g/kg.body weight. The comparable toxicity LD₅₀ for aspirin is about 1.75g/kg. body weight. Because of their low toxicity, in addition to topicalapplication, they may also be administered orally or parenterally. Suchparenteral application may take the form (a) of ear, eye and nasal drops(all in suitable carrier vehicles); (b) of injections, whetherintramuscular, intravenous, intraarticular or subcutaneous; (c) ofsuppositories, both anal and vaginal; (d) anemas and vaginal douches aswell as (e) catamenial and non-catamenial tampons.

Insofar as is presently known, the following brief remarks may be madeabout the theory underlying the utility of the amido compounds of thisinvention as analgesics. It will be understood that it is not intendedthat the invention be limited by the theory offered.

Thus, there is increased awareness nowadays of the biochemical nature ofthe sensation of pain. Pain results from certain prostaglandin compoundswhich are produced in vivo by the action of the enzyme prostaglandinsynthetase upon arachidonic acid, an unsaturated fatty acid. Manytraditional non-steroidal analgesics such as acetylsalicylic acid(aspirin) are believed to exert their analgesic action by the inhibitionof prostaglandin synthetase activity or inactivation of prostaglandinsas formed in situ or both. Thus, Norton, W. L. and Meisinger, M. A. P.state in "Inflammation", 1977, 2, No. 1, pp. 37 to 46 at p. 42 thatnon-steroidal anti-inflammatory agents probably exert analgesic activitythrough prostaglandin synthesis inhibition, via a peripheral antiedemaeffect, a direct decrease in the pain-promoting effects ofprostaglandins, or both. See generally, Wax, J., Winder, C. V., Tessman,D. K., and Stephens, M. D., 1975. "A sensitive Method for theComparative Bioassay of Nonsteroidal Anti-inflammatory Compounds inAdjuvant-induced Primary Inflammation in the Rat." J. Pharmacol. Exp.Ther. 192: 166; Winter, C., and Flataker, L., 1965. "NociceptiveThresholds as Affected by Parenteral Administration of Irritants and ofVarious Antinociceptive Drugs". J. Pharmacol. Exp. Ther. 148: 373; andCollier, H. O. J., Dinneen, L. C., Johnson, C. A., and Schneider, C.,1968. "The Abdominal Constriction Response and its Suppression byAnalgesic Drugs in the Mouse". Br. J. Pharmacol. Chemother. 32: 295.

The unique distance of separation and spatial orientation of the twoortho substituents on a benzene ring of aspirin are believed to providethe necessary ability to inhibit the action of prostaglandin synthetaseor prostaglandins themselves or both.

As stated above, the salicylamides of Formula I are known and describedin existing literature. A representative, though not the only availableor conceivable method of synthesis thereof is disclosed in U.S. Pat. No.4,287,191. The succeeding description has been adopted from U.S. Pat.No. 4,287,191. In general such compounds can be prepared by reacting alower alkyl (R_(a)) salicylate ester with an acyl chloride (R_(x) COCl)in the presence of a Lewis acid to form an ester of a 5-acylsalicylicacid. The 5-acylsalicylic acid ester is then hydrolyzed and theresulting free acid is reacted with a substituted amine or aniline H₂N--R₃ to form the 5-acylsalicylamide. The term "lower alkyl" as usedherein means alkyl of from 1 through 4 carbon atoms. R_(x) is n--C₇ inthe case of APCF3-8 and AMCF3-8. It is n--C₉ in the case of AN-10. It isn-C₈, n-C₉ and n-C₁₅ in the cases involving ACBXE-9, ABC-4 and RV-19respectively. In the cases of SAN-6 and S-4-F, the Friedel-Craftsacylation step is replaced by a Friedel-Crafts alkylation process bysubstituting the acid chloride R_(x) --CO--Cl by a normal alkyl halideR_(x) Cl. In the cases of SAN-6 and S-4-F which are prepared by way ofthe Friedel-Crafts alkylation initial step, R_(x) is C₆ and C₄respectively. R₃ is a substituted benzene ring or a thiazole or abenzothiazole ring. In the case of a substituted benzene ring, thesubstituents may be --NO₂ in a para position or --COOC₂ H₅ in a metaposition or --CF₃ in either a para or a meta position. When R₃ is one ofthe two heterocyclic attachments mentioned above, the linking thereof tothe secondary amido nitrogen atom occurs through the No. 2 carbon atomof the heterocyclic attachment. Acryloyl AN-10 is, as already notedabove, an acrylic acid derivative of AN-10 wherein the 2-hydroxy groupof AN-10 is replaced by the CH₂ ═CH--COO--group. Such replacement isaccomplished by the esterification of AN-10 in the manner generallyemployed for the esterification of phenols. Thus, esterification ofAN-10 with acryloyl chloride in pyridine or other base results in theesterified product, i.e., acryloyl AN-10.

As a usual procedure, the 5-acyl or 5-alkyl salicylic acid precursor isprepared in a medium or reaction solvent which is customarily consideredsuitable for the conductance of a Friedel-Crafts acylation or alkylationwith optimal yield, minimal side reactions, non-onerous reactionconditions and minimal reaction time. A preferred reaction solvent iscarbon disulfide. Anhydrous aluminum chloride or other Lewis acid isinitially added to the carbon disulfide and the mixture is cooled, e.g.with ice. A solution of the alkyl salicylate ester, e.g. methylsalicylate, and an acyl halide, e.g. a chloride (or an alkyl halide asapplicable) in carbon disulfide or other reaction solvent is then slowlyadded and the temperature is maintained below about 10° C. Aftercompletion of reaction which may take as long as 24 hours, the reactionmass is poured into ice water and the mixture is then extracted with asuitable solvent such as ether. The ether or other extract is washedwith water and then dried over anhydrous sodium sulfate. Thereafter, theether or other solvent is evaporated in vacuo. The resulting solidresidue is dissolved in a suitable solvent such as ethanol and treatedwith a solution of an alkali metal hydroxide, e.g. 2N NaOH solution.After heating to a temperature of between about 80° and 120° C., e.g. ona steam bath, the mass is cooled and acidified with a suitable acid suchas HCl to a pH of about 1 to precipitate the product. Recrystallizationfrom ethanol gives purified 5-acylsalicylic acid or 5-alkylsalicylicacid, depending on whether an acid halide or an alkyl halide was theinitial Friedel-Crafts reactant.

The 5-acyl or 5-alkyl salicylic acid is reacted with the appropriatesubstituted aniline or other amine, e.g. p-nitroaniline in the case ofAN-10, in a suitable reaction solvent such as chlorobenzene. Desirablythe 5-acyl or 5-alkylsalicylic acid is pre-reacted with phosphorustrichloride in the solvent at a suitable temperature, e.g. between about55° C. and about 80° C. The reaction time is usually between about oneand about five hours. The solution is then cooled and the appropriatesubstituted aniline or heterocyclic amine, e.g. p-nitroaniline is thenadded and the solution is again heated to a suitable temperature, e.g.between about 55° C. and about 80° C. as previously described for aboutone to about five hours and is then refluxed until the reaction iscomplete, e.g. for about 24 hours. The solvent is then removed in vacuoand the residue is purified by recrystallization from a mixture of asuitable solvent such as a mixture of ethanol and water. The resultingproduct is an amido compound of the invention.

Detailed descriptions of the methods of synthesis of5-n-decanoylsalicylic acid and of AN-10 therefrom are given in Examples1 and 2 of U.S. Pat. No. 4,287,191.

Example 3 of U.S. Pat. No. 4,287,191 describes toxicity tests for AN-10performed upon sixteen female white rats of average weight 265 gms.Example 3 concludes with the finding that LD₅₀ for AN-10 by the singledose oral route is greater than 2000 mg./kg. in Osborne-Mendel whiterats.

Such descriptions are hereby incorporated by reference herein. Examples1 through 3 of U.S. Pat. No. 4,287,191 are adopted as Examples 1 through3 hereof.

Methods of synthesis of the other preferred compounds of the invention,namely APCF3-8, AMCF3-8, SAN-6, S-4-F, ACBXE-9, ABC-4 and RV-19 follownaturally from the method of synthesis described for AN-10 withappropriate substitution of the respective reactants. See generally,Batista, A. J., "Salicylanilides: Design, Synthesis, and In VitroEvaluation as Inhibitors of Dental Plaque-Forming Microorganisms", Ph.D.Dissertation, State University of New York at Buffalo, 1980. AcryloylAN-10 is prepared, as already noted above, from AN-10 by esterificationof the phenolic --OH group of AN-10 with acryloyl chloride in pyridine.

EXAMPLES 4, 5 AND 6 AND CONTROL EXAMPLE 7

In a group of 5 male outbred hairless mice, inflammation is induced ontheir ears by the topical application thereto of 4.0 nmole in acetonesolution (total volume 10 microliter) of the known divalent calciumionophore (antibiotic A-23187), which is derived from Streptomyceschartreusis and is a member of a known class of compounds showingionophoric activity. See, e.g. Pressman, B. C., "Biological Applicationsof Ionophores", Ann. Rev. Biochem., 45, 501, 1976. Said compound hasbeen found, in in vivo tumor promotion studies involving topicalapplication thereof to mice backs to have potent ability to cause skinirritation with white blood cell infiltration, erythema (skinreddening), edema, epidermal hypertrophy and subsequent epidermalhyperplasia. See Marks, F., Furstenberger, G., and Kownatzki, E.,"Prostaglandin E-mediated Mitogenic Stimulation of Mouse Epidermis invivo by divalent cation ionophore A-23187 and by tumor promoter12-O-tetradecanoyl phorbol-13-acetate, Cancer Res., 41, 696, 1981.

In each animal only one ear is treated, the other untreated ear servingas a control.

Acute inflammation develops on treated mice ears within 4 hoursfollowing topical application of A-23187, showing both time and dosedependencies. Topical application of steroidal (hydrocortisone) andnon-steroidal (indomethacin) anti-inflammatory compositions 30 minutesafter application of said ionophore causes reduction of inflammation.

In Examples 4, 5 and 6 the compounds AN-10, APCF3-8 and AMCF3-8,respectively, are topically applied to the treated ears of differentgroups of five male outbred hairless mice 30 minutes following thetopical application thereto of the ionophore A-23187. Specifically, 1.5micromole of the amido compound in acetone solution (total volume 10microliters) is applied topically to treated male outbred hairless miceears 30 min. after topical application thereto of a calcium ionophore(A-23187, 4.0 nmole total volume to 10 microliter) in acetone. Asalready noted, in each case, each animal serves as its own control inthat only one ear is subjected to said test regime while the other earis left untouched. Erythema and edema are assessed 4 hrs. afterapplication of the ionophore. In Control Example 7,3,4',5-tribromosalicylanilide (TBS) is applied in the same manner.

TBS is structurally very similar to the compounds of Formula I wherein--R₁ and --R₂ are each --Br and --R₃ is a parabromo substituted benzenering.

The varying degrees of effectiveness of AN-10, APCF3-8, AMCF3-8 and TBSin the above-described tests are summarized in Table 1 below.

                  TABLE I                                                         ______________________________________                                        ANTI-INFLAMMATORY ACTIVITY OF SELECTED                                        AMIDO COMPOUNDS ON INFLAMMATION OF MICE EARS                                  CAUSED BY CALCIUM IONOPHORE (A-23187)                                                           Reduction in                                                                             Reduction in                                     Amido Compounds   Edema (%)  Erythema (%)                                     ______________________________________                                        Example 4                                                                             AN-10         59         59                                           Example 5                                                                             APCF3-8       48         57                                           Example 6                                                                             AMCF3-8       80         76                                           Control TBS           12         35                                           Example 7                                                                     ______________________________________                                    

From the data summarized in Table 1, of the four amido compounds testedfor anti-inflammatory activity, only TBS (which is not one of thecompounds of the present invention) is essentially inactive at theconcentration used, whereas AN-10, APCF3-8 and AMCF3-8 are all effectiveanti-inflammatories. Of the two isomers APCF3-8 and AMCF3-8 (whichdiffer from each other in the position of the --CF₃ group), the metaisomer has a significantly higher level of activity, i.e., the metaisomer shows about 30% more edema reduction activity and about 20% moreerythema reduction activity than the para isomer.

This fact is suggestive of a structure/function relationship in theinflammation reduction and/or inhibition process. Along the same linesit may be speculated as a theory underlying the mode of action of thesalicylamides of Formula I, that the relative ineffectiveness of TBS isdue to the decreased lipophilicity of such compound when alkyl, alkanoylor similar --R₁ and --R₂ attachments (as already defined above) aresubstituted by --Br thereby leading to decreased dermal penetration.

EXAMPLES 8 THROUGH 14

Acute inflammation is induced by the application of 4 nano mole of theantibiotic A-23187 to the ears of young, male, adult hairless outbredmice (Skh:hr-1 strain). Thereafter, one of the compounds AN-10, AMCF3-8,ACBXE-9, acryloyl AN-10, S-4-F and SAN-6 is applied to the affected earsand the degree of reduction in edema (inflammation) noted.

The method used in the subject Examples differs from the method used inthe preceding Examples (4 through 7) in two respects. Firstly, in thesubject Examples test animals are assigned to different treatment groupsin which each ear of an animal receives the same assigned treatment,i.e., the test animals of the subject Examples do not serve as their owncontrols as they do in the preceding four Examples.

Secondly, in the expression of the data, the objective parameter of earweights is used as the sole data source (for the reduction of edema) aserythematous responses are not recorded. Ear weights are determined bysacrificing the animals four hours after initial application of theantibiotic A-23187 or other control material by the use of CO₂ gas.Thereafter, the ears are excised by cutting along the characteristicridge readily discernible along the inner aspect of the ears. Wet anddry ear weights are used to determine the extent of the edema orinflammation present.

In Study A, 28 test animals are randomized into four treatment groups ofseven each and subjected to the following ear treatment regimen:

Group A--A-23187

Group B--A-23187+AN-10

Group C--AN-10

Group D--Acetone

Each animal is dosed with a treatment consisting of a 10 microliterquantity of the assigned test material solution (or pure acetone in thecase of the animals of Group D) applied to the outer aspect of bothears, i.e., 10 microliter of test material per ear. The concentrationsof the respective materials in acetone solution are such that a 10microliter dose of a solution of the antibiotic A-23187 contains 4 nanomole of such antibiotic. The corresponding quantity in the case of theAN-10 in acetone solution is 1.5 micromole. The animals of Groups A andB are initially treated with the acetone solution of A-23187. In thecase of the animals of Group B alone, 10 microliter of the acetonesolution of AN-10 is applied to the affected ears 1/2 hour after theapplication of the above-mentioned quantity of a solution in acetone ofthe antibiotic A-23187. The animals of Group C receive a 10 microliterdose per ear of the AN-10 in acetone solution alone. The animals ofGroup D receive a dose of 10 microliter per ear of pure acetone. All thetest subjects are sacrificed four hours after the application of A-23187to the animals of Groups A and B or the other test materials in the caseof the animals of Groups C and D. The results are summarized in Table 2noted below.

A second group of studies (Study B) is conducted on two consecutive dayswith two sets of mice (totalling 80 animals) received from the sameshipment.

The first batch of 40 animals is divided into 8 groups of 5 each. On Day1, the six salicylamides AN-10, AMCF3-8, ACBXE-9, acryloyl AN-10, S-4-Fand SAN-6 are applied as test solutions to the untreated ears of eachgroup of 5 animals to ascertain whether or not any of the compoundspossesses inflammatory potential. The remaining two groups of 5 animalseach serve as controls and their ears are dosed with A-23187 and acetonerespectively. The respective quantities of the test and controlmaterials and the methanol of administration is identical with thatdescribed for Study A. It is found that none of the six compounds beingtested cause any noticeable inflammation.

On Day 2, using the second set of 40 mice, sub-divided into 8 groups of5 each, the six compounds in question are applied as acetone solutionsin the manner described under Study A to mice ears inflamed with A-23187again, as described in Study A above. As with the studies conducted onDay 1, the remaining two groups of 5 animals each serve as controls andtheir ears are dosed with A-23187 and acetone respectively.

The amount of each salicylamide compound applied is kept constant, forDays 1 and 2, at 1.5 micromole per 10 microliter of test solution.Sacrifice begins four hours after application A-23187, on both days, andthe results are recorded. Table 2 summarizes the results of the regimenof testing involved with each one of the 30 animals in question on Day 2with the remaining 10 animals serving as controls as already noted.Table 2 shows the reduction in edema observed with the use of each oneof the six salicylamide compounds tested.

                  TABLE 2                                                         ______________________________________                                                         Reduction in Edema (%)                                       Example(s)                                                                             Compound      Study A    Study B                                     ______________________________________                                        8 and 9  AN-10         55         81                                          10       Acryloyl AN-10                                                                              *          82                                          11       AMCF3-8       *          81                                          12       ACBXE-9       *          76                                          13       S-4-F         *          70                                          14       SAN-6         *          59                                          ______________________________________                                         *Not Tested                                                              

Examination of the above data indicates that all six of the salicylamidecompounds tested, An-10, acryloyl AN-10, AMCF3-8, ACBXE-9, S-4-F andSAN-6 exhibit significant antiinflammatory activity under the testconditions.

The variations noted in the activity levels for AN-10 are probably theresult of individual differences between the 5 animals tested on Day 1and the 5 animals tested on Day 2 as well as possible non-uniformity oftesting conditions on the days in question. It is believed that suchdifferences may be minimized and possibly eliminated by making use of alarger number of animals in each test group and by conducting such testsat the same time and under as uniform conditions as possible.

EXAMPLE 15

An ointment is prepared incorporating the compound AN-10 as an activeingredient. The ointment comprises the respective ingredients in thepercentages shown below:

    ______________________________________                                        Ingredient        wt. %                                                       ______________________________________                                        AN-10             1                                                           Anhydrous wool fat                                                                              2                                                           Viscous paraffin  10                                                          White petroleum jelly                                                                           to 100                                                      ______________________________________                                    

AN-10 is substituted by an equivalent quantity of any one of thecompounds of Formula I, e.g., APCF3-8, AMCF3-8, ACBXE-9, acryloyl AN-10,S-4-F and SAN-6 as well as mixtures thereof to form comparableointments.

The resulting ointment is applied on the skin to relieve a painful orinflammatory condition thereof in sufficient amount to cause thespreading of 0.01 microgram to 500 microgram of the active compound persquare centimeter of the dermal area affected.

The relief of pain and inflammation results. Advantageously, theointment is applied to the affected area of the skin every four totwelve hours when pain persists.

EXAMPLE 16

An ointment of comparable efficacy to that described in Example 15 ismade with the following ingredients:

    ______________________________________                                        Ingredient         wt. %                                                      ______________________________________                                        Compound of Formula I                                                                            1                                                          Cetyl alcohol      2.4                                                        Anhydrous wool fat 1                                                          Viscous paraffin   15                                                         White petroleum jelly                                                                            to 100                                                     ______________________________________                                    

The resulting ointment is applied to the skin to relieve inflammationcaused by a painful skin condition in the manner described in Example15.

EXAMPLE 17

The compositions of this invention are also formulated into a solidform. Such forms have use as a stick-type composition intended forapplication to the lips or other parts of the body. Such compositionsconsist essentially of from 0.001% to 10%, preferably 0.01% to 5% of acompound of Formula I, e.g., acryloyl AN-10 and from 50% to 98%,preferably 60% to 90% of an emollient. This composition can furtherconsist essentially of from 1% to 20%, preferably 5% to 15% of asuitable thickening agent, and optionally emulsifiers and water.Thickening agents include without limitation: cross-linked carboxypolymethylene polymers, methylcellulose, gum tragacanth, gum kharaya,xanthan gums and bentonite. Suitable emulsifers are of anonionic-anionic or cationic variety. Examples of suitable nonionicemulsifiers include fatty alcohols having 10 to 20 carbon atoms, fattyalcohols having 10 to 20 carbon atoms condensed with 2 to 20 moles ofethylene oxide or propylene oxide, alkyl phenols with 6 to 12 carbonatoms in the alkyl chain condensed with 2 to 20 moles of ethylene oxide,mono- and di-fatty acid esters of ethylene glycol wherein the fatty acidmoiety contains from 10 to 20 carbon atoms, fatty acid monoglycerideswherein the fatty acid moiety contains from 10 to 20 carbon atoms,diethylene glycol, glycerol, sorbitol, sorbitan, polyoxyethylenesorbitol, polyoxyethylene sorbitan, and hydrophilic wax esters. Suitableanionic emulsifiers include the fatty acid soaps, e.g., sodium,potassium and triethanolamine soaps, wherein the fatty acid moietycontains from 10 to 20 carbon atoms. Other suitable anionic emulsifiersinclude the alkali metal, ammonium or substituted ammonium alkylsulfates, alkyl arylsulfonates, and alkyl ethoxy ether sulfonates having10 to 30 carbon atoms in the alkyl moiety. The alkyl ethoxy ethersulfonates contain from 1 to 50 ethylene oxide units. Satisfactorycationic emulsifiers are the quaternary ammonium, morpholinium andpyridinium compounds. Certain of the emollients noted below also haveemulsifying properties.

Suitable emollients include lanolin and its derivatives, namely:lanolin, lanolin oil, lanolin wax, lanolin alcohols, lanolin fattyacids, isopropyl lanolate, ethoxylated lanolin, ethoxylated lanolinalcohols, ethoxylated cholesterol, propoxylated lanolin alcohols,acetylated lanolin, acetylated lanolin alcohols, lanolin alcoholslinoleate, lanolin alcohols ricinoleate, acetate of lanolin alcoholsricinoleate, acetate of ethoxylated alcohols-esters, hydrogenolysisproducts of lanolin, ethoxylated hydrogenated lanolin, ethoxylatedsorbitol lanolin, and liquid and semi-solid lanolin absorption bases.

Additives commonly found in topical compositions such as preservatives,e.g., methyl and ethyl paraben, dyes and perfume are advantageouslyincluded in any of the afore-described compositions.

An exemplary solid stick according to this invention containing one ormore of the compounds of Formula I is prepared by shaping and moldingthe following ingredients:

    ______________________________________                                        Ingredient       Wt. %                                                        ______________________________________                                        APCF3-8          1                                                            Carnauba wax     40                                                           Lecithin         40                                                           Methyl cellulose 10                                                           Glycerol         5                                                            Water            to 100                                                       ______________________________________                                    

The resulting solid stick of this Example is applied upon the skin torelieve pain or inflammation in substantially the same manner as withthe ointment described in Example 15.

EXAMPLE 18

Capsules containing one or more compounds of Formula I are prepared byconventional methods. Accordingly, 300 milligrams of APCF3-8 isincorporated within the two halves of a quasi cylindrical gelatinousmaterial which are held together with a friction fit. Said capsulehalves are heat sealed for added benefit.

Said gelatinous material is alternatively substituted by a conventionalnon-toxic material which dissolves or disintegrates within thealimentary canal.

Two capsules made according to this Example are administered orally fourtimes daily to substantially reduce the pain associated with a painfulcondition of the alimentary canal, e.g, peptic ulcers and foodallergies.

The foregoing list of ailments is merely illustrative and not limitativeof the utility of capsules prepared according to the present invention.

EXAMPLE 19

One or more of the compounds of Formula I are also administered orallyin the form of tablets.

A tablet suitable for oral administration is prepared from 300milligrams of AMCF3-8, by the addition of 25 milligrams of starch or awater soluble gum (other pharmaceutically acceptable binding substancesalso being suitable) and formed into the shape of a tablet bycompression within a suitable die.

The resulting tablets are administered orally for the relief of pain inthe same manner as that described for the capsules of Example 18 and forthe relief of pain resulting from the same conditions.

EXAMPLE 20

The compositions of this invention are also formulated in a solutionform. The solution form of the composition consists essentially of from0.001% to 10%, preferably 0.01% to 5% of a compound of Formula I, e.g.,ACBXE-9 and the balance being a suitable organic solvent. Suitableorganic materials useful as the solvent or a part of a solvent systemare as follows: propylene glycol, glycerine, ethanol, sorbitol esters,1,2,6-hexanetriol, isopropanol, diethyl tartrate, butanediol, andmixtures thereof. Such solvent systems can also contain water.

Accordingly, a solution is prepared as follows:

    ______________________________________                                        Ingredient       Wt. %                                                        ______________________________________                                        Propylene glycol 10                                                           Glycerine        27                                                           ACBXE-9          1                                                            Ethanol          50                                                           Water            to 100                                                       ______________________________________                                    

The solution is applied to the affected skin in substantially the samemanner as that described for the ointment of Example 15.

EXAMPLE 21

The solution of Example 20 is incorporated in a closed metal containerfitted with an aerosol cap and pressurized using conventional methods upto 100 psi. pressure with butane gas. The resulting aerosol is used as aconvenient method of administering an anti-inflammatory composition ofthe present invention namely, one or more compounds of Formula I, e.g.,ACBXE-9 for the relief of painful skin conditions. The composition ofthe aerosol is applied to the affected area of the skin at periodicintervals for the relief of inflammation or pain, and preferably, everyfour to twelve hours.

EXAMPLE 22

The compositions of this invention are also formulated in a cream form.The creams consist essentially of from 0.001% to 10%, preferably 0.01%to 5% of a compound or compounds of Formula I, e.g., S-4-F, from 5% to50%, preferably 10% to 25% of an emollient, and the balance water. Theemollients described above with respect to the compositions of theinvention in a stick form (Example 17) are equally suitable herein.Optionally, the cream form contains a suitable emulsifier. Theemulsifiers described in Example 17 above are also equally suitableherein. When an emulsifier is included, it is in the composition at alevel from about 2% to about 10%, preferably 5%.

A cream is prepared by mixing together the following ingredients:

    ______________________________________                                        Ingredient         Wt. %                                                      ______________________________________                                        S-4-F              1                                                          Ethoxylated cholesterol                                                                          20                                                         Sorbitol           5                                                          Water              to 100                                                     ______________________________________                                    

The resulting cream is applied to the skin to relieve pain andinflammation in the same manner as that described for the ointment ofExample 15.

EXAMPLE 23

A lotion is prepared incorporating one or more compounds of Formula I,e.g., SAN-6 by mixing together the following ingredients in the statedpercentages on a wt/wt basis:

    ______________________________________                                        Ingredient            Wt. %                                                   ______________________________________                                        SAN-6                 1                                                       Viscous paraffin oil  10                                                      Ethanol               2                                                       Glycerol              1                                                       Propylene glycol      2                                                       Sorbic Acid           0.15                                                    Mixture of cetylstearyl alcohol                                                                     0.5                                                     and sodium cetylstearylsulfate                                                and a non-ionic emulsifier                                                    Perfume oil of Lily of the Valley                                                                   0.1                                                     Water                 to 100                                                  ______________________________________                                    

In an advantageous alternative embodiment, the above lotion contains 5wt.% of a sun screen, e.g., para-amino benzoic acid or PABA at theexpense of the water ingredient.

The resulting lotion is topically applied to relieve pain andinflammation of the skin in the same manner as that described for thecream of Example 22.

EXAMPLE 24

One or more compounds of Formula I, e.g., AN-10 are formulated into agel form by simply admixing a suitable thickening agent with theabove-described solution composition of Example 20. Examples of suitablethickening agents include: cross-linked carboxy polymethylenecopolymers, methyl cellulose, gum tragacanth, gum kharaya, xanthan gumsand bentonite. The gelled compositions consist essentially of from0.001% to 10%, preferably 0.01% to 5% of a compound or compounds ofFormula I, from 5% to 75% preferably 10% to 50% of an organic solvent,0.5% to 20%, preferably 1% to 10% of the aforementioned thickeningagent, the balance being water. Suitable organic solvents includewithout limitation glycerine, sorbitol esters, 1,2,6-hexanetriol,ethanol, isopropanol, diethyl tartrate, butanediol, and mixturesthereof.

A gel is prepared by mixing together the following ingredients:

    ______________________________________                                        Ingredient       Wt. %                                                        ______________________________________                                        AN-10            1                                                            1,2,6-hexanetriol                                                                              45                                                           Bentonite        8                                                            Water            to 100                                                       ______________________________________                                    

The resulting gel is applied to the skin to relieve pain or inflammationin the same manner as that described for the cream of Example 22 notedabove.

EXAMPLE 25

A liniment is prepared from a gel composition of Example 24.

In the aforementioned gel composition, the presence of the bentonitethickening agent is eliminated and the balance is made up with1,2,6-hexanetriol.

The resulting liniment is applied to the skin to relieve pain andinflammation in the same manner as that noted for the gel of Example 24.

EXAMPLE 26

One or more compounds of Formula I, e.g., AN-10 may be incorporated intosolution or suspension form for the purpose of administration by way ofinjections, whether intravenous, intramuscular, subcutaneous,intraarticular or otherwise.

A suitable solution is prepared in an aqueous vehicle which contains thefollowing ingredients in milligrams per milliliter of solution:

    ______________________________________                                        Ingredients        Milligrams per milliliter                                  ______________________________________                                        AN-10              1                                                          Isotonic sodium chloride solution                                                                30                                                         Dextrose           2                                                          Invert sugar       2                                                          Sodium lactate     30                                                         Lactic acid        30                                                         Water              to 100                                                     ______________________________________                                    

The resulting solution is suitable for administration by way ofsubcutaneous, intramuscular, intraarticular and intravenousadministration.

Such solution is also suitable for administration to the gums by way ofsubcutaneous injections in preparation for dental surgery.

EXAMPLE 27

One or more of the compounds of Formula I, e.g., APCF3-8 areincorporated in an aqueous suspension for, e.g., deep intramuscular orintraarticular injection purposes.

A suitable, aqueous injectable suspension is prepared which contains thefollowing ingredients:

    ______________________________________                                        Ingredients      Milligrams per milliliter                                    ______________________________________                                        APCF3-8          1                                                            Sodium citrate   5                                                            Citric acid      5                                                            Carboxymethylcellulose                                                                         0.6                                                          Lecithin         6                                                            Povidone         0.3                                                          Methylparaben    1                                                            Propylparaben    0.1                                                          Sorbitan monopalmitate                                                                         0.5                                                          Polyoxyethylene sorbitan                                                                       0.5                                                          monopalmitate                                                                 Water            to 100                                                       ______________________________________                                    

An intramuscular injection of about 1 to about 2 milliliters of saidsuspension is effective in relieving systemic pain particularly at theinjection site.

An intraarticular injection of comparable quantity relieves pain inskeletal joints and surrounding areas as a result of various conditions.Non-limiting examples of such conditions include arthritis, tendonitisand rheumatism.

EXAMPLES 28 AND 29

One or more compounds of Formula I, such as AMCF3-8 is incorporated in asuppository for intraanal use.

A suppository is prepared by mixing together the following ingredientsin the weight ratios shown:

    ______________________________________                                        Ingredients   Percent by Weight                                               ______________________________________                                        AMCF3-8       1                                                               Cocoa butter  93                                                              Zinc oxide    3                                                               Menthol       2                                                               Balsam Peru   1                                                               ______________________________________                                    

Said suppository is prepared by melting the cocoa butter base at atemperature of about 39° C. and adding the remaining ingredients,including AMCF3-8 to the melt, with blending, to provide a homogeneoussystem. The cocoa butter based resulting melt is poured into molds ofappropriate dimensions and allowed to solidify. The resulting product isa lubricious suppository which melts at body temperature to release theAMCF3-8 or other salicylamide compound to provide improvedanti-inflammatory benefits.

Intraanal administration of the resulting suppository is effective inrelieving anal pain and inflammation. The application is repeated asnecessary.

A vaginal suppository is made generally following the proceduredescribed above for making an anal suppository. The vaginal suppositoryhas the composition noted below:

    ______________________________________                                        Ingredients             Milligrams                                            ______________________________________                                        AMCF3-8                 1                                                     Glycerine               5                                                     Glyceryl monopalmitate  3                                                     Glyceryl monostearate   3                                                     Hydrogenated palm kernel oil fatty acids                                                              50                                                    Hydrogenated coconut oil fatty acids                                                                  to 100                                                ______________________________________                                    

In place of AMCF3-8, any one or more of the compounds of Formula I maybe employed.

Intravaginal administration of the resulting suppository is effective inrelieving vaginal pain and inflammation. The application is repeated asnecessary.

In view of the highly anti-microbial nature of AMCF3-8 and the othercompounds of Formula I, the elimination of fungal infections such asmonilia is also accomplished with the use of the vaginal suppository ofthis Example.

Comparable benefits with respect to vaginitis are obtained with the useof said suppository.

EXAMPLE 30

An aqueous preparation containing one or more of the compounds ofFormula I, such as acryloyl AN-10 is incorporated in an aqueouscomposition to form a douche for intravaginal administration. Acomposition is prepared which contains the following ingredients in theweight percentages shown below:

    ______________________________________                                        Ingredients      wt. %                                                        ______________________________________                                        Acryloyl AN-10   1                                                            Acetic acid      6                                                            Sodium acetate   6                                                            Water            to 100                                                       ______________________________________                                    

Said composition advantageously further incorporates inert butpharmaceutically acceptable coloring matter and fragrances.

The use of the resulting composition as an intravaginal douche resultsin the alleviation of intravaginal pain and inflammation.

In view of the highly anti-microbial nature of the compounds to FormulaI, substantial benefit with respect to bacterial infections such asmonilia and vaginitis is also obtained.

EXAMPLE 31

One or more compounds of Formula I such as S-4-F is incorporated in ashampoo for application to the scalp.

A shampoo is prepared by dissolving one part by weight of S-4-F in 10parts by weight of ethanol and incorporating the resulting solution in ashampoo base. The shampoo base contains the following ingredients:

    ______________________________________                                        Ingredients             wt. %                                                 ______________________________________                                        Polyoxyethylene sorbitan monostearate                                                                 70                                                    Triethanolamine lauryl sulfate                                                                        10                                                    Water                   20                                                    ______________________________________                                    

One part by weight of the S-4-F in ethanol solution is added to nineparts by weight of the above-described shampoo base to form a medicatedshampoo.

Pain and inflammation of the scalp is effectively alleviated by the useof such shampoo with repeat applications as needed.

EXAMPLE 32

Soaps containing one or more of the compounds of Formula I are preparedas a further vehicle for the topical administration of said compounds.

A commercially available bar of soap consisting of a predominantquantity of the sodium or potassium salts of various fatty acids or ofalkali metal isethionates is melted with mild heating.

To 99 parts by weight of the melted soap, one part by weight of SAN-6 isadded with stirring.

Said soap and SAN-6 mixture is thereafter made into soap bars by any ofthe conventional methods employed for that purpose including, e.g.,extrusion into the form of a rod, followed by cutting into billets andthe stamping of the resulting billets into tablets of soap.Alternatively, the molten soap and SAN-6 mixture may simply be pouredinto molds and permitted to solidify.

The resulting medicated soap is used in the washing of affected areas ofthe skin or for general purpose bathing to bring about relief of painand inflammation of the skin.

The use of such soap is also beneficial in preventing or eliminatingacne and infections of the skin in view of the highly anti-microbialnature of the compounds of Formula I.

EXAMPLE 33

The compounds of Formula I are incorporated in a suitable lubricatingbase to form an enema.

An enema is prepared by the incorporation of a 10% solution in ethanolof AN-10 in a castor oil base. The ratio of the ethanol solution tocastor oil is 1:9.

The administration of one to ten milliliters of the resultingcomposition by way of intraanal syringe results in the relief of rectalpain.

EXAMPLES 34, 35 AND 36

Medicated ear drops containing one or more of the compounds of Formula Isuch as AN-10 are prepared by the mixing together of the followingingredients in the parts by weight noted below:

    ______________________________________                                        Ingredient                wt. %                                               ______________________________________                                        AN-10                     1                                                   Triethanolamine polypeptide oleate-condensate                                                           10                                                  Chlorbutanol              0.5                                                 Propylene glycol          to 100                                              ______________________________________                                    

The administration of the resulting ear drops into the ear cavity orauditory canal, with repeated applications as needed, results in therelief of painful conditions of the ear, including but not limited to,pain which is solely the result of dermal inflammation.

Nose drops containing one or more of the compounds of Formula I such asAPCF3-8 are prepared by mixing such compound together with the otheringredients in the proportions noted below:

    ______________________________________                                        Ingredient          wt. %                                                     ______________________________________                                        APCF3-8             1                                                         Essential oil of cajeput                                                                          0.5                                                       Essential oil of eucalyptus                                                                       0.5                                                       Essential oil of peppermint                                                                       0.5                                                       Cottonseed oil      to 100                                                    ______________________________________                                    

Administration of three to four drops in each nostril of nose drops ofthe composition noted above three to four times daily results in therelief of pain and inflammation of skin and the nasal mucous membranes.

The composition described above may alternatively be incorporated into acompressed air nebulizer and administered in like manner with equalefficacy.

Eye drops containing one or more of the compound of Formula I such asACBXE-9 are prepared by mixing together the following ingredients in theproportions noted below:

    ______________________________________                                        Ingredient          wt. %                                                     ______________________________________                                        ACBXE-9             1                                                         Ethyl alcohol       0.5                                                       Thimerosal (preservative)                                                                         0.001                                                     Propylene glycol    10                                                        Sodium chloride     3                                                         Water               to 100                                                    ______________________________________                                    

The application of one or two drops of eye drops of the abovecomposition, repeated as required, is effective in reducing andeliminating pain and inflammation. In view of the anti-microbialproperties of the compounds of Formula I, eye infections are alsoeffectively abated or prevented.

EXAMPLES 37 AND 38

Medicated sanitary napkins, medicated pads and medicated dressings areprepared by the incorporation of one or more of the compounds of FormulaI in a suitable cotton wool or other absorbent article.

A sanitary napkin is prepared in accordance with the method described inExample 3 of U.S. Pat. No. 4,226,237.

The resulting sanitary napkin is sprayed with a 10% wt./wt. acryloylAN-10 in acetone solution to insure a concentration spread of 0.01 gramAN-10 per square centimeter of the napkin. After drying in an aeratedchamber at room temperature the napkin is hermetically sealed in apolyethylene or metal foil envelope.

The resulting pad is effective in relieving pain and inflammation whenused as a medicated pad.

A pad is prepared in a size other than that to which the teachings ofU.S. Pat. No. 4,226,237 are confined to thereby produce a medicated pador a medicated dressing for use in the bandaging of wounds, lacerations,and other conditions of the skin which cause pain.

The resulting pads and dressings when made of selected differingdimensions are effective in relieving pain and inflammation when used asmedicated pads and as medicated dressings.

EXAMPLES 39 AND 40

One or more compounds of Formula I, such as acryloyl AN-10 areincorporated in plasters and bandages.

To this purpose, a plaster or a bandage is sprinkled with a 10% wt./wt.acryloyl AN-10 in acetone solution to the extent of 0.01 gram acryloylAN-10 per square centimeter of surface area. Following drying in anaerated chamber at room temperature, the resulting plasters and bandagesare stored in hermetically sealed polyethylene or metal foil envelopesto prevent loss of the salicylamide compound from the medicated plasteror medicated bandage.

The term plaster as used herein means a wound dressing which has anadhesive coated on one side thereof. Advantageously, the adhesivematerial is one which is not affected by the acryloyl AN-10 in acetonesolution. The term bandage as used herein means a roll of cotton orother fabric of sterile nature without the incorporation therein of anadhesive which is used in the dressing of wounds.

The acryloyl AN-10 impregnated plaster or bandage is used with enhanced,therapeutic value when utilized in the dressing of wounds by minimizingor eliminating the pain associated with wounds, lacerations,inflammation and like conditions.

EXAMPLES 41 AND 42

One or more of the compounds of Formula I, such as S-4-F areincorporated in a catamenial or non-catamenial tampon.

A catamenial tampon is prepared in accordance with the method describedin U.S. Pat. No. 4,226,237, of the kind shown in the illustrativeembodiments included in FIGS. 8 and 10 thereof.

The outer surface of said catamenial tampon is sprinkled with a 10%wt./wt. acetone solution of S-4-F in an amount sufficient to provide aconcentration of 0.01 gram of such compound per square centimeter of theouter surface of such tampon. Following drying in an aerated chamber atroom temperature, the tampon is stored in a sealed polyethylene or metalfoil pouch, in order to guard against the loss of any S-4-F compoundprior to the use of such tampon.

When the resulting catamenial tampon is intrravaginally worn, relief ofintravaginal pain and inflammation is noticed. Additionally, in view ofthe highly anti-microbial nature of the compounds of Formula I,including S-4-F, bacterial conditions such as monilia are effectivelycombated and prevented.

When said tampon is prepared in appropriate (smaller) dimensions, suchas to enable the same to fit snugly within other body cavities such asthe ears and the nose without causing any discomfort to the wearer,similar relief from pain and inflammation of skin as well as affectedmucous membranes is noticed. As an added benefit the effective combatingor elimination of microbial infections is also noticed as a result ofthe highly anti-microbial nature of compounds of Formula I.

As will be readily apparent to persons of ordinary skill in the art towhich the present invention pertains, various modifications of suchinvention as hereinbefore set forth and as further defined in theappended claims may be made without departing from the spirit and scopethereof regardless of the applicability of the theoretical basesadvanced herein in elucidation of the invention.

What is claimed is:
 1. A method for treating dermatological inflammationin a mammal, which comprises the topical application to the affectedarea of the skin of an amount effective to ameliorate the inflammatorycondition of an anti-inflammatory composition having an octanol/waterdistribution function of about 4.5 to about 10 which comprises, inadmixture a pharmaceutically acceptable carrier vehicle and ananti-inflammatorily effective amount of a compound of the formula:##STR25## wherein the lipophilicity imparting substituents --R₁ and --R₂which impart an octanol/water distribution function of about 4.5 toabout 10 to said compound are --H, normal or branched chain or cyclic orfused ring polycyclic or non-fused ring polycyclic alkyl, alkenyl,alkynyl, or aryl groups optionally containing further substituentsthereon, said --R₁ and --R₂ substituents comprising up to about 30carbon atoms when taken together either attached directly to the phenylring provided with an amido and a hydroxyl group in an ortho orientationwith respect to each other or attached to said phenyl ring through a##STR26## group with the proviso that --R₁ and --R₂ are not both --H andwherein --R₃ is selected from the group consisting of R₄ -substitutedphenyl wherein R₄ is selected from the group consisting of --OH, --COOH,the tautomeric pair ##STR27## --CH₂ COOH, --COOCH₃, --COOC₂ H₅, --CH₂COOCH₃, --CH₂ COOC₂ H₅, --NO₂, and CX₁ X₂ X₃ wherein X₁, X₂ and X₃ arehalogen atoms.
 2. A method of alleviating pain in a mammal, whichcomprises the systemic administration of an analgesically effectiveamount of an anti-inflammatory composition having an octanol/waterdistribution function of about 4.5 to about 10 which comprises, inadmixture a pharmaceutically acceptable carrier vehicle and ananalgesically effective amount of a compound of the formula: ##STR28##wherein the lipophilicity imparting substituents --R₁ and --R₂ whichimpart an octanol/water distribution function of about 4.5 to about 10to said compound are --H, normal or branched chain or cyclic or fusedring polycyclic or non-fused ring polycyclic alkyl, alkenyl, alkynyL, oraryl groups optionally containing further substituents thereon, said--R₁ and --R₂ substituents comprising up to about 30 carbon atoms whentaken together either attached directly to the phenyl ring provided withan amido and a hydroxyl group in an ortho orientation with respect toeach other or attached to said phenyl ring through a ##STR29## groupwith the proviso that --R₁ and --R₂ are not both --H and wherein --R₃ isselected from the group consisting of R₄ -substituted phenyl wherein R₄is selected from the group consisting of --OH, --COOH, the tautomericpair ##STR30## --CH₂ COOH, --COOCH₃, --COOC₂ H₅, --CH₂ COOCH₃, --CH₂COOC₂ H₅, --NO₂, and CX₁ X₂ X₃ wherein X₁, X₂ and X₃ are halogen atoms.3. The method of claims 1 or 2 wherein X₁, X₂ and X₃ are identicalhalogen atoms.
 4. The method of claim 3 wherein X₁, X₂ and X₃ arefluorine atoms.
 5. The method of claims 1 or 2 wherein R₃ is R₄-substituted-phenyl and R₄ is selected from the group consisting of--NO₂ and --CF₃.
 6. The method of claim 5 wherein R₄ is meta--CF₃. 7.The method of claim 5 wherein R₄ is in the para position.
 8. The methodof claims 1 or 2, wherein the compound is selected from the groupconsisting of a compound of the formula: ##STR31## wherein (a) R₁ isn-decanoyl and R₃ is p-nitrophenyl;(b) R₁ is n-octanoyl and R₃ isp-trifluoromethylphenyl; (c) R₁ is n-octanoyl and R₃ ism-trifluoromethylphenyl; (d) R₁ is n-hexyl and R₃ is p-nitrophenyl; (e)R₁ is n-butyl and R₃ is m-trifluoromethylphenyl; (f) R₁ is n-nonanoyland R₃ is m-carbethoxyphenyl; (g) R₁ is n-decanoyl and R₃ isp-nitrophenyl;and mixtures thereof.
 9. The method of claims 1 or 2wherein said carrier vehicle comprises a material selected from thegroup consisting of white petroleum jelly, viscous paraffin, cetylalcohol, anhydrous wool fat and mixtures thereof.
 10. The method ofclaims 1 or 2 wherein said carrier vehicle comprises a material selectedfrom the group consisting of carnauba wax, lecithin, methyl cellulose,glycerol, water and mixtures thereof.
 11. The method of claims 1 or 2wherein said compound is present in said carrier vehicle in the range offrom about 0.1 to about 50 micrograms per milliliter of said carriervehicle.
 12. The method of claim 2 wherein the mammal is a human being.13. A method for treating dermatological inflammation in a mammal, whichcomprises the topical application to the affected area of the skin of anamount effective to ameliorate the inflammatory condition of ananti-inflammatory composition having an octanol/water distributionfunction of about 4.5 to about 10 which comprises, in admixture apharmaceutically acceptable carrier vehicle and an anti-inflammatorilyeffective amount of a compound of the formula: ##STR32## wherein thelipophilicity imparting substituent --R₁ which imparts an octanol/waterdistribution function of about 4.5 to about 10 to said compound is anormal or branched chain or cyclic or fused ring polycyclic or non-fusedring polycyclic alkyl, alkenyl, alkynyl, or aryl group optionallycontaining further substituents thereon, said --R₁ substituentcomprising up to about 30 carbon atoms either attached directly to thephenyl ring provided with an amido and a hydroxyl group in an orthoorientation with respect to each other or attached to said phenyl ringthrough a ##STR33## group and wherein --R₃ is selected from the groupconsisting of R₄ -substituted phenyl wherein R₄ is selected from thegroup consisting of --OH, --COOH, the tautomeric pair ##STR34## --CH₂COOH, --COOCH₃, --COOC₂ H₅, --CH₂ COOCH₃, --CH₂ COOC₂ H₅, --NO₂, and CX₁X₂ X₃ wherein X₁, X₂ and X₃ are halogen atoms.
 14. A method ofalleviating pain in a mammal, which comprises the systemicadministration of an analgesically effective amount of a compositionhaving an octanol/water distribution function of about 4.5 to about 10which comprises, in admixture a pharmaceutically acceptable carriervehicle and an analgesically effective amount of a compound of theformula: ##STR35## wherein the lipophilicity imparting substituent --R₁which imparts an octanol/water distribution function of about 4.5 toabout 10 to said compound is a normal or branched chain or cyclic orfused ring polycyclic or non-fused ring polycyclic alkyl, alkenyl,alkynyl, or aryl group optionally containing further substituentsthereon, said --R₁ substituent comprising up to about 30 carbon atomseither attached directly to the phenyl ring provided with an amido and ahydroxyl group in an ortho orientation with respect to each other orattached to said phenyl ring through a ##STR36## group and wherein --R₃is selected from the group consisting of R₄ -substituted phenyl whereinR₄ is selected from the group consisting of --OH, --COOH, the tautomericpair ##STR37## --CH₂ COOH, --COOCH₃, --COOC₂ H₅, --CH₂ COOCH₃, --CH₂COOC₂ H₅, --NO₂, and CX₁ X₂ X₃ wherein X₁, X₂ and X₃ are halogen atoms.15. The method of claim 13 wherein X₁, X₂ and X₃ are identical halogenatoms.
 16. The method of claim 15 wherein X₁, X₂ and X₃ are fluorineatoms.
 17. The method of claim 13 wherein R₃ is R₄ -substituted-phenyland R₄ is selected from the group consisting of --NO₂ and --CF₃.
 18. Themethod of claim 17 wherein R₄ is meta-CF₃.
 19. The method of claim 17wherein R₄ is in the para position.
 20. The method of claim 13 whereinthe compound is selected from the group consisting of a compound of theformula: ##STR38## wherein (a) R₁ is n-decanoyl and R₃ isp-nitrophenyl;(b) R₁ is n-octanoyl and R₃ is p-trifluoromethylphenyl;(c) R₁ is n-octanoyl and R₃ is m-trifluoromethylphenyl; (d) R₁ isn-hexyl and R₃ is p-nitrophenyl; (e) R₁ is n-butyl and R₃ ism-trifluoromethylphenyl; (f) R₁ is n-nonanoyl and R₃ ism-carbethoxyphenyl; or (g) R₁ is n-decanoyl and R₃ is p-nitrophenyl;ormixtures thereof.
 21. The method of claim 13 wherein said carriervehicle comprises a material selected from the group consisting of whitepetroleum jelly, viscous paraffin, cetyl alcohol, anhydrous wool fat andmixtures thereof.
 22. The method of claim 13 wherein said carriervehicle comprises a material selected from the group consisting ofcarnauba wax, lecithin, methyl cellulose, glycerol, water and mixturesthereof.
 23. The method of claim 13 wherein said compound is present insaid carrier vehicle in the range of from about 0.1 to about 50micrograms per milliliter of said carrier vehicle.
 24. The method ofclaim 14 wherein the mammal is a human being.
 25. The method of claim 1or 13 wherein the mammal is a domestic animal.
 26. The method of claim 1or 13 wherein the mammal is a human being.
 27. The method of claim 1 or13 which comprises repeated topical applications of said composition tothe affected areas of the skin at spaced apart intervals of time. 28.The method of claim 27 which comprises applications of said compositionto the affected area of the skin every 4 to 12 hours.
 29. The method ofclaim 12 or 24 wherein the administration is oral.
 30. The method ofclaim 12 or 24 wherein the administration is intravenous.
 31. The methodof claim 12 or 24 wherein the administration is intramuscular.
 32. Themethod of claim 12 or 24 wherein the administration is intraarticular.33. The method of claim 12 or 24 wherein the administration issubcutaneous.
 34. The method of claim 12 or 24 wherein the human beingis suffering from an ear ache, and the composition is in the form of eardrops and the administration is topical into the affected ear.
 35. Themethod of claim 12 or 24 wherein the human being is suffering from eyeinflammation or pain, the composition is in the form of eye drops andthe administration is topical into the affected eye.
 36. The method ofclaim 12 or 24 wherein the human being is suffering from nasal pain orinflammation, the composition is in the form of nasal drops and theadministration is intranasal.
 37. The method of claim 12 or 24 whereinthe human being is suffering from anal pain or inflammation, thecomposition is in the form of anal supporitories and the administrationis intraanally.
 38. The method of claim 37 wherein the human being issuffering from rectal pain, the composition is in the form of an aqueoussolution or suspension and the administration is as an enema.
 39. Themethod of claim 12 or 24 wherein the human being is suffering fromvaginal pain or inflammation, the composition is in the form of vaginalsuppositories and the administration is intravaginal.
 40. The method ofclaim 39 wherein the human being is suffering from vaginal pain orinflammation, the composition is in the form of a douche and theadministration is intravaginal.
 41. The method of claim 39 wherein thehuman being is suffering from a vaginal microbial infection, thecomposition is in the form of a douche and the administration isintravaginal.
 42. The method of claim 39 wherein the composition is inthe form of vaginal suppositories and the administration isintravaginal.
 43. The method of claim 12 or 24 wherein the human beingis suffering from pain or inflammation of the skin, the composition isin a form suitable for topical application and the administration istopical.
 44. The method of claim 2 or 14 wherein the mammal is adomestic animal.
 45. The method of claim 44 wherein the administrationis oral.
 46. The method of claim 44 wherein the administration isintravenous.
 47. The method of claim 44 wherein the administration isintramuscular.
 48. The method of claim 44 wherein the administration issub-cutaneous.
 49. The method of claim 44 wherein the administration isintraarticular.
 50. The method of claim 44 wherein the domestic animalis suffering from a painful or inflammatory condition of the ear, thecomposition is in the form of ear drops and the administration istopical into the affected ear.
 51. The method of claim 44 wherein thedomestic animal is suffering from eye inflammation or pain, thecomposition is in the form of eye drops and the administration istopical into the affected eye.
 52. The method of claim 44 wherein thedomestic animal is suffering from nasal pain or inflammation, thecomposition is in the form of nasal drops and the administration isintranasal.
 53. The method of claim 44 wherein the domestic animal issuffering from anal pain or inflammation, the composition is in the formof anal suppositories and the administration is intraanally.
 54. Themethod of claim 44 wherein the domestic animal is suffering from rectalpain, the composition is in the form of an aqueous solution orsuspension and the administration is as an enema.
 55. The method ofclaim 44 wherein the domestic animal is suffering from vaginal pain orinflammation, the composition is in the form of vaginal suppositoriesand the administration is intravaginal.
 56. The method of claim 44wherein the domestic animal is suffering from vaginal pain orinflammation, the composition is in the form of a douche and theadministration is intravaginal.
 57. The method of claim 55 wherein thedomestic animal is suffering from a vaginal microbial infection, thecomposition is in the form of a douche and the administration isintravaginal.
 58. The method of claim 55 wherein the composition is inthe form of vaginal suppositories and the administration isintravaginal.
 59. The method of claim 44 wherein the domestic animal issuffering from pain or inflammation of the skin, the composition is in aform suitable for topical application and the administration is topical.60. The method of claim 24 wherein X₁, X₂ and X₃ are identical halogenatoms.
 61. The method of claim 24 wherein R₃ is R₄ -substituted-phenyland R₄ is selected from the group consisting of --NO₂ and --CF₃.
 62. Themethod of claim 24, wherein the compound is selected from the groupconsisting of a compound of the formula: ##STR39## wherein (a) R₁ isn-decanoyl and R₃ is p-nitrophenyl;(b) R₁ is n-octanoyl and R₃ isp-trifluoromethylphenyl; (c) R₁ is n-octanoyl and R₃ ism-trifluoromethylphenyl; (d) R₁ is n-hexyl and R₃ is p-nitrophenyl; (e)R₁ is n-butyl and R₃ is m-trifluoromethylphenyl; (f) R₁ is n-nonanoyland R₃ is m-carbethoxyphenyl; or (g) R₁ is n-decanoyl and R₃ isp-nitrophenyl;or mixtures thereof.
 63. The method of claim 24 whereinsaid carrier vehicle comprises a material selected from the groupconsisting of white petroleum jelly, viscous paraffin, cetyl alcohol,anhydrous wool fat and mixtures thereof.
 64. The method of claim 24wherein said carrier vehicle comprises a material selected from thegroup consisting of carnauba wax, lecithin, methyl cellulose, glycerol,water and mixtures thereof.
 65. The method of claim 24 wherein saidcompound is present in said carrier vehicle in the range of from about0.1 to about 50 micrograms per milliliter of said carrier vehicle.